Lee, HyunbeomLe, Hoang
V.Wu, RuiDoud, EmmaSanishvili, RuslanKellie, John F.Compton, Phillip
D.Pachaiyappan, BoobalanLiu, DaliKelleher, Neil L.Silverman, Richard B.Mechanism of Inactivation of GABA Aminotransferase
by (<i>E</i>)- and (<i>Z</i>)‑(1<i>S</i>,3<i>S</i>)‑3-Amino-4-fluoromethylenyl-1-cyclopentanoic
AcidWhen
γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter
in the mammalian central nervous system, falls below a threshold level,
seizures occur. One approach to raise GABA concentrations is to inhibit
GABA aminotransferase (GABA-AT), a pyridoxal 5′-phosphate-dependent
enzyme that degrades GABA. We have previously developed (1<i>S</i>,3<i>S</i>)-3-amino-4-difluoromethylene-1-cyclopentanoic
acid (CPP-115), which is 186 times more efficient in inactivating
GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT.
We also developed (<i>E</i>)- and (<i>Z</i>)-(1<i>S</i>,3<i>S</i>)-3-amino-4-fluoromethylenyl-1-cyclopentanoic
acid (<b>1</b> and <b>2</b>, respectively), monofluorinated
analogs of CPP-115, which are comparable to vigabatrin in inactivating
GABA-AT. Here, we report the mechanism of inactivation of GABA-AT
by <b>1</b> and <b>2</b>. Both produce a metabolite that
induces disruption of the Glu270–Arg445 salt bridge to accommodate
interaction between the metabolite formyl group and Arg445. This is
the second time that Arg445 has interacted with a ligand and is involved
in GABA-AT inactivation, thereby confirming the importance of Arg445
in future inactivator design.CPP;metabolite formyl group;acid;GABA;vigabatrin;inactivation;future inactivator design;inactivating;Arg 4452015-09-18